Disorders associated with cephalic pain can fall into any of a wide variety of classes including, for example, vascular headaches (e.g., a migraine headache), tension headaches, headaches associated with the use a substance or its withdrawal, and trigeminal autonomic cephalalgias. The trigeminal autonomic cephalalgias often induce some of the most severe types of cephalic pain of any disorder associated with cephalic pain. Examples of trigeminal autonomic cephalalgias are episodic and chronic cluster headaches, episodic and chronic paroxysmal hemicranias, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
Cluster headaches (also known as migrainous neuralgia, Horton's syndrome, Raeder's syndrome, sphenopalatine neuralgia, and histaminic cephalalgia) are recurrent headaches characterized by sudden onset and intense pain on one side of the face that begins around the eye, temple, or cheek. There are two clinical patterns of cluster headaches: episodic and chronic. About 80-90% of patients with cluster headaches have them in episodic patterns which are characterized by one to three short attacks, e.g., lasting from fifteen minutes to three hours, of pain around the eyes per day which are grouped or “clustered” over a stretch of one to two months and then followed by a pain-free remission period. Typically, the remission period lasts for at least one month and often up to a year. The remaining 10% of patients with cluster headaches have them in chronic patterns which are characterized by daily occurrences of headaches lasting for more than a year with no remission period or with remission periods lasting less than one month. Isselbacher, K. J. et al. (eds). Harrison's Principles of Internal Medicine, Thirteenth Edition (1994, McGraw-Hill, New York, N.Y.), pp. 69-70. A single person may experience alternating episodic and chronic phases of cluster headaches.
While the underlying cause of cluster headaches is unknown, the occurrence of such headaches is correlated with abnormal activation of the posterior hypothalamus. May, A. et al. (1998) Lancet 352(9124):275-278. Abnormal hypothalamic activation then does two things. First, it activates the trigeminal nerve, causing pain in the trigeminal distribution. Second, it causes sympathetic dysfunction in the form of drooping eyelid and constricted pupil, and parasympathetic overactivity that is responsible for the runny eye and stuffy nose that accompany most attacks. Sewell, R. A., Halpern, J. H. “Response of Cluster Headache to Psilocybin and LSD.” in Winkelman, M. J. et al. eds. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments (Greenwood Publishing Group, New York, 2007).
Because the pain of a cluster headache comes on suddenly and may subside within a short time, over-the-counter pain relievers such as aspirin or ibuprofen are not effective in treating the pain. The headache is usually gone before these medications can provide pain relief. At present, there are several different approaches for providing acute pain relief for patients suffering from cluster headaches. These approaches include: (1) treatment comprising inhalation of oxygen; (2) treatment with an oral, injectable, or inhalable (e.g., as a nasal spray) form of a triptan; (3) treatment with an intravenous, injectable, or inhalable form of an ergot derivative; (4) treatment with an injectable form of a synthetic somatostatin; and (5) treatment using nasal drops of local anesthetics. All of these acute treatments have disadvantages. For example, while inhalation of 100% oxygen through a mask can provide dramatic relief for most who use it, it can be extremely inconvenient to have to carry around an oxygen cylinder and regulator. In addition, use of triptans is not recommended for people with uncontrolled high blood pressure or ischemic heart disease. While intravenous treatment with ergot derivatives can be fast acting, it must be provided in a doctor's office. Moreover, inhaled versions of ergot derivatives work more slowly and may not provide pain relief in a relevant time frame. Synthetic somatostatins and local anesthetics work for some people but are not reliably effective.
For patients with chronic cluster headaches who do not respond to any of these treatment approaches and, who if left without treatment often kill themselves (hence the informal term of “suicide headache” to characterize a cluster headache), surgery may be indicated. Sewell, R. A., Halpern, J. H. “Response of Cluster Headache to Psilocybin and LSD.” in Winkelman, M. J. et al. eds. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments (Greenwood Publishing Group, New York, 2007). Candidates for surgery must have headaches only on one side of the head because the surgery can be performed only once. Several types of surgery have been used to treat cluster headaches and they typically involve procedures attempting to damage the nerve pathways thought to be the immediate cause of the pain. The most common of these procedures are directed at the trigeminal nerve and include conventional surgery, in which the surgeon cuts part of the trigeminal nerve with a scalpel or uses small burns to destroy part of the nerve, and radiosurgery, in which the surgeon using a focused beam of radiation to destroy part of the trigeminal nerve. Residual muscle weakness in the jaw and sensory loss in certain areas of the face and head often make these procedures options of last resort. Cohen, A. S. et al. (June 2007) Headache 969-980; Franzini, A. et al. (May 2003) Neurosurgery 52(5):1095-1099.
There are also various options for short-term and long-term prevention of cluster headaches. These treatment options, which also all have disadvantages, include: (1) treatment with corticosteroids (indicated for short term use only as they have serious side effects (e.g., immunosuppression, osteoporosis, cataracts, and psychosis) if used long-term; (2) treatment with ergot derivatives, provided sublingually or rectally (indicated for short term use of two to three weeks only); (3) treatment with injectable nerve blockers (indicated for short-term use and must be administered in a doctor's office); (4) treatment with anticonvulsants (indicated for both short and long term use); (5) treatment with methysergide (indicated for short term use only as prolonged treatment has been associated with rare fibrotic conditions); (6) treatment with calcium channel blockers (indicated for both short and long term use but has many side effects including dizziness, nausea, fatigue, swelling of the ankles and low blood pressure); (7) treatment with serotonin agonists (insurance generally covers only a handful of injections per month, not the required several a day, and the too frequent use of such compounds can have cardiac implications); (8) treatment with lithium (indicated for long term use but has many side effects such as tremor, increased thirst, diarrhea and drowsiness and can cause kidney and thyroid damage). Cohen, A. S. et al. (June 2007) Headache 969-980; Sewell, R. A., Halpern, J. H. “Response of Cluster Headache to Psilocybin and LSD.” in Winkelman, M. J. et al. eds. Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments (Greenwood Publishing Group, New York, 2007); http://www.mayoclinic.com/health/cluster-headache/DS00487. Thus, there exists a need for new medications and methods of treatment and/or prevention using medications which avoid some of the disadvantages experienced by patients using these traditional treatment methods.